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Validation of Fibroblast-Derived PI16 as a Novel Target for pain Treatment

Award Number: R01NS116704
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2020
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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Validation of Fibroblast-Derived PI16 as a Novel Target for pain Treatment - PROJECT SUMMARY/ABSTRACT Chronic pain and the addictive effects of opioids used to control pain are major health problems affecting millions of Americans. Validation of novel targets for the safe treatment of chronic pain is urgently needed. We identified peptidase inhibitor 16 (PI16) as a novel regulator of chronic pain in an unbiased RNA seq screen. PI16 is a putative peptidase inhibitor that has not been studied in the context of pain. We showed that male and female Pi16-/- mice are protected against mechanical allodynia in the spared nerve injury (SNI) and paclitaxel models of neuropathic pain. Along the neuraxis, PI16 is only detectable in fibroblasts around peripheral nerves (perineurium), and in the meninges of dorsal root ganglia (DRG), spinal cord, and brain, but not in neurons, glia or leukocytes. . PI16 levels in perineurial and DRG meningeal fibroblasts increase during neuropathic pain. The overall objective of this project is to validate PI16 as a novel target for the treatment of chronic pain using mouse models and human tissues of neuropathy patients and controls and to identify the underlying mechanisms. Our central hypothesis is that increased PI16 secretion by DRG meningeal and perineurial fibroblasts promotes chronic pain by increasing blood nerve barrier (BNB) permeability and leukocyte trafficking into nerve and DRG. The significance is in the validation of PI16 as a novel, potentially druggable, regulator of chronic pain and the discovery of fibroblasts as key regulators of chronic pain. We propose the following three specific aims: 1. Validate the key role of PI16 in chronic pain. In two independent laboratories, we will test the hypothesis that genetic deletion of Pi16 in male and female mice protects against chronic pain in well-established models of chronic pain. 2. Investigate expression and regulation of PI16 in fibroblasts around mouse DRG and mouse and human peripheral nerves. The hypothesis is that PI16 production by fibroblasts in DRG meninges and perineurium is increased via a TGFβ− and Epac1-mediated pathway to promote chronic pain. We will use tissues from the neuraxis in mouse pain model and nerves from humans with neuropathic pain. 3. Determine the contribution of PI16 to blood nerve barrier integrity in mouse pain models and in a human in vitro model. Using a model of the human BNB, we will test the hypothesis that PI16 increases BNB permeability and leukocyte transmigration. Using co-immuno-precipitation and mass spectrometry we will identify novel PI16 targets. This proposal is conceptually innovative because successful completion will validate PI16 as a novel key regulator of neuropathic and inflammatory pain and establish a novel role of perineurial fibroblasts in regulating BNB function with major consequences for chronic pain. The expected findings are significant because they will advance our fundamental understanding of cellular and molecular mechanisms that contribute to chronic pain and will identify a novel target for treatment of pain that is not expressed in the brain, and therefore is unlikely to lead to addiction.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = -$160,002 )
2026	2024	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Drug Use and Addiction Research Programs	000	2	10/1/2025	EXTENSION WITH OR WITHOUT FUNDS	-$160,002
														Subtotal = -$160,002

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Drug Use and Addiction Research Programs	001	2	3/19/2025	EXTENSION WITH OR WITHOUT FUNDS	$160,002
2025	2020	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/19/2025	NEW	-$160,002
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $675,862 )
2024	2024	THE UNIVERISTY OF TEXAS MD ANDERSON CANCER CENTER, A COMPONENT OF THE UNIVERISTY OF TEXAS SYSTEM	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Drug Use and Addiction Research Programs	000	2	7/15/2024	EXTENSION WITH OR WITHOUT FUNDS	$675,862
														Subtotal = $675,862

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/4/2022	NEW	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $2,908,421 )
2020	2020	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/16/2020	NEW	$2,908,421
														Subtotal = $2,908,421

Grand Total All Awards = $3,424,282

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Validation of Fibroblast-Derived PI16 as a Novel Target for pain Treatment

Award Number: R01NS116704

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/30/2020

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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